JPH0597845A - Condensed diazepinone and medicine contain- ing same - Google Patents

Abstract

PURPOSE: To provide the new condensed diazepinones which are most suitable to cure diseases of the central nervous system, to promote the cerebral blood flow, and particularly to cure Alzheimer's disease.

CONSTITUTION: The condensed diazetinones of formula I and the salts thereof with inorganic or organic acids, e.g. 5, 11-dihydro-11-[[4-[3-[(2,2-dimethyl-1- oxobutyl)-ethylamino]propyl]-1-piperidinyl]acetyl]-6H- pyrido[2,3-6][1,4]benzodiazepin-6-one, are obtained, for example, by allowing the base substitute condensed diazepinone of formula VI to react with carboxylic acid expressed by the formula; R²-COOH or its reactive derivative in a solvent at temp. up to the b.p. of the reaction mixture. In the formula I, B is formulae II (wherein R³, R⁴ are each H, a halogen, methyl, etc.), III (wherein R⁵ is H, Cl, etc.), IV (wherein R⁶, R⁷ are each H, an alkyl, R⁷ is a halogen), or V; (l) is 1 to 3; (m) is 1 or 2; (n) is 1 to 4; R¹ is H, an alkyl; R² is H, an alkyl, alkenyl, phenyl, phenylalkyl.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel fused diazepinones, methods for their preparation and agents containing these compounds for treating central nervous system disorders and promoting cerebral blood flow.

[0002]

BACKGROUND OF THE INVENTION Condensed diazepinones having antiulcer properties and gastric juice secretion inhibiting effects are disclosed in European Patent Applications Nos. 39519 and 57428, and U.S. Pat. No. 3691159, No. 42139
No. 84, No. 4213985, No. 4210648, No. 4410527
No. 4424225, No. 4442222 and No. 4424226.
Already known from the specification. Regarding fused diazepinones, European Patent Application No. 156191 (U.S. Pat.
And European Patent Application No. 312895 show quite different pharmacological properties compared to the compounds of the above mentioned publications, i.e. the beneficial effect on heart rate is derived by introducing alkylaminoacyl or dialkylaminoacyl groups. It describes that you can do it. This is European Patent Application No. 213293
No. 254955, No. 273239, No. 3066698, German Patent Application No. 3800986, No. 3802334, No. 381944.
The same applies to the compounds of No. 4, No. 3820346 and No. 3820345. The compounds of these publications have been used in human and veterinary medicine for their beneficial effects on heart rate and in view of their lack of inhibitory effect on gastric and salivary secretions and mydriatic effect. Suitable for use as a vagal pacemaker to treat pulse and bradyarrhythmias. European Patent Application No. 402734 describes fused diazepinones as agents for treating diseases of the central nervous system and promoting cerebral blood flow. These agents are suitable for use in geriatrics and also for treating migraine. Some of the compounds described in that patent show good CNS efficacy and therefore can be used to treat diseases of the central nervous system, especially Alzheimer's disease. According to conventionally derived structure-activity relationships, the presence of a terminal basic N atom in the side chain is known to be essential for muscarinic antagonists with high M ₂ selectivity (US No. 4550107, European Patent Application No. 402734 and Engel et al., J. Med. Chem. 32: 1718 (1989)).

[0003]

Surprisingly, by acylating the basic nitrogen atom at the end of the side chain linked to the amino nitrogen of the diazepinone ring, M having high affinity can be obtained.
It has been found that it is possible to obtain a _2-selective muscarinic antagonist. Further, the “carboxamide” of the present invention is
It shows a much better M ₂ / M ₁ ratio compared to previously described M ₂ selective antagonists. That is, the novel compounds show a significantly favorable ratio of binding affinity for the M ₂ receptor over the M ₁ receptor. The compounds of the present invention are
_{2 In} view of its selectivity, it can be used to treat bradycardia and bradyarrhythmias in human and veterinary medicine. In view of their beneficial effects on cerebral blood flow, these compounds are particularly suitable for use in geriatrics and for the treatment of migraine. Animal (rat) As seen in the experiments, they enhance the learning capacity of old animals. The novel fused diazepinones of the present invention are, in some cases, highly lipophilic and therefore have good brain efficacy (cerebro-a).
vailability) is met. At the same time, this high lipophilicity results in a rapid drop in blood levels, which means that it does not affect heart rate. M ₂ -selective antagonists with favorable CNS penetration and at the same time M ₂ / M ₁ selectivity are particularly suitable for treating diseases of the central nervous system, in particular Alzheimer's disease. The fused diazepinones of the present invention have the general formula I:

[0004]

[Chemical 6]

(In the formula, B represents one of divalent groups represented by the following formula,

[0006]

[Chemical 7]

And X, l, m, n and R ^{1 to} R ⁷ are as defined below, where X is a ═CH— group, or B is a divalent group (S). X may also represent a nitrogen atom, l represents an integer 1, 2 or 3, m represents an integer 1 or 2, n represents an integer 1 to 4, R ¹ represents a hydrogen atom or a straight chain. or it represents a branched C _1-6 alkyl group, R ² represents a hydrogen atom; substituted by C _1-3 alkyl group as required; linear or branched C _1-8 alkyl group; a linear or branched C _4-6 alkenyl group good C _{3- 7} also be a cycloalkyl group; an adamantyl group; a methyl group in an aromatic group, or required by, one necessary or two optionally substituted phenyl group by a methyl or methoxy group or a halogen atom Or substituted by a methoxy group or a halogen atom Represents a phenylalkyl group having 1-3 carbon atoms in the alkylene moiety can have, R ³ and R ⁴ may be the same, even if also different, a hydrogen atom or a halogen atom or a methyl Group, an ethyl group, a methoxy group or an ethoxy group, R ⁵ represents a hydrogen atom, a chlorine atom or a methyl group, R ⁶ and R ⁷ may be the same or different, and a hydrogen atom Or a C _1-3 alkyl group, but R ⁷ may further represent a halogen atom).

Preferred compounds of the above general formula I are those in which X is a nitrogen atom, B is a divalent group (S), and l is a number 2.
, M is the number 1, n is the number 3 or 4, R
¹ is a linear C _1-4 alkyl group, R ² is a branched C _4-6 alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, methylcyclopentyl group, methylcyclohexyl group, methyl A cycloheptyl group or an adamantyl group, R ³
And R ⁴ represents a hydrogen atom, or one of these groups represents a methyl group or a halogen atom, and a substituent — (CH ₂ ) _n —N
R ¹ -CO- R ² is a compound bonded to the 4-position of the piperidinyl ring. Particularly preferred compounds are those in which R ¹ represents an ethyl group. Examples of the branched alkyl group or alkenyl group are 1-methyl-ethyl group, 1,1-dimethyl-ethyl group, 1,1-dimethyl-propyl group, 1,1.
-Dimethyl-butyl group, 1,1,3-trimethyl-butyl group, 1-ethyl-1-methyl-ethyl group, 1-ethyl-1-methyl-propyl group, 1-ethyl-1-methyl-
Butyl group, 1-ethyl-1,3-dimethyl-butyl group,
1-propyl-1-methyl-ethyl group, 1-propyl-
1-methyl-propyl group, 1-propyl-1-methyl-
Butyl group, 1-ethyl-ethyl group, 1,1-diethyl-
It includes an ethyl group, a 1,1-diethyl-propyl group, a 1,1-dimethyl-butyl group and a 1,1-dimethyl-3-butenyl group. The invention also relates to acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, malic acid, citric acid, tartaric acid. According to the invention, the novel acylated diazepinones of general formula I are obtained by the following method. a) General formula II:

[0009]

[Chemical 8]

A base-substituted fused diazepinone of the formula (wherein X, B, l, m, n and R ¹ are as defined above) is represented by the general formula III: R ² --CO--OH (III) Wherein R ² is as defined above), or a reactive derivative thereof. Examples of reactive derivatives of carboxylic acids of general formula III are:
It includes its esters such as methyl ester, ethyl ester or benzyl ester, thioesters such as methylthioester or ethylthioester, halides such as acid chlorides, its acid anhydrides and imidazolides. The reaction is carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,
Dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activator or dehydrating agent, such as ethyl chloroformate,
Thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonylimidazole or N,
In the presence of N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvent. Below, it is conveniently carried out at temperatures between -25 and 150 ° C, preferably between -10 ° C and the boiling temperature of the solvent used. The reaction may also be carried out without solvent, and the water produced during the reaction is further azeotropically distilled, for example by heating with toluene using a water separator, or magnesium sulphate or molecular weight. It may be separated by addition of a desiccant such as a sieve. For example, the reaction is carried out using an acid halide in an inert solvent such as ether, toluene, methylene chloride and the like, at a temperature of -50 ° C to the boiling point of the reaction mixture, preferably a temperature of 0 ° C to 50 ° C, preferably Can be carried out in the presence of hydrogen halide binders such as tertiary amines, sodium carbonate or calcium carbonate. Not only free amines of general formula II can be used, but also their salts, from which the amines are liberated in situ by the auxiliary base to which they are added. The reaction may be carried out at reflux temperature in a high boiling solvent such as xylene in the presence of, for example, an imidazolide or carbodiimide. b) General formula IV:

[0011]

[Chemical 9]

A diazepinone of the formula where X and B are as previously defined is represented by the general formula V:

[0013]

[Chemical 10]

Where l, m, n, R ¹ and R ² are as defined above, and Nu is a nucleating group.
ofugic group), which represents a leaving group), is acylated with a carboxylic acid derivative. The reaction of the compound of general formula IV with the acid derivative of general formula V is carried out by known methods. The leaving group Nu is a group which, together with the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative. Examples of reactive carboxylic acid derivatives are acid halides, esters, anhydrides or mixed anhydrides (these being, for example, salts and acid chlorides of the corresponding acids (Nu = OH), for example phosphorus oxychloride, diphosphorus). Produced from acid tetrachloride or chloroformates, or N-alkyl-2-acyloxypyridinium salts, which have the general formula V (Nu = O
Produced when the compound of H) is reacted with an N-alkyl-2-halopyridinium salt).

The reaction is preferably carried out using a strong inorganic acid, especially a mixed acid anhydride of dichlorophosphoric acid.
The reaction may be carried out in the presence of an acid binder (proton acceptor), if necessary. Examples of suitable proton acceptors are alkali metal carbonates or bicarbonates, such as sodium carbonate or potassium bicarbonate; tertiary organic amines such as pyridine, triethylamine, ethyldiisopropylamine, 4- (dimethylamino) pyridine; or It is sodium hydride. The reaction is -2
It is carried out in an inert solvent at a temperature of 5 ° C to 130 ° C. Examples of inert solvents are chlorinated aliphatic hydrocarbons such as methylene chloride, 1,2-dichloroethane; open chain ethers or cyclic ethers such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons such as benzene. , Toluene, xylene, o-dichlorobenzene; polar aprotic solvents such as acetonitrile,
Dimethylformamide or hexamethylphosphoric triamide; or mixtures thereof. The reaction time depends on the type and amount of the acylating agent of the general formula V used and is 15
It ranges from minutes to 80 hours. It is not necessary to prepare compounds of general formula V in pure form. Alternatively, they may be produced in situ in the reaction mixture by known methods.

The bases of the general formula I thus obtained may subsequently be converted into their acid addition salts, and if acid addition salts are obtained, they are free base or other pharmacologically acceptable. It may be converted into an acid addition salt. The novel fused diazepinones of general formula I according to the invention contain up to two independent chiral carbon atoms. The acylated tricyclic compound itself can be considered as another chiral element, which may occur in two mirror image symmetric forms. The nature of the tricyclics determines whether this central inversion energy barrier is stable enough for the individual isomers to be room temperature, yet isolatable. In compounds of general formula I in which X is a nitrogen atom and the position adjacent to the diazepinone ring is unsubstituted, the required activation energy is that the diastereomer can no longer be detected and is alone at room temperature. It was found to be reduced to the extent that it was isolated by preparative isolation. Thus, the novel fused diazepinones of general formula I of the present invention contain up to three independent chiral elements, one of which is not structurally stable under ambient conditions and under certain circumstances. Therefore, compounds of this type may occur in many diastereomeric forms and / or as enantiomeric (+) and (−) forms. The present invention includes not only the individual isomers, but also mixtures thereof. Diastereomers can be separated based on their different physicochemical properties, for example by fractional recrystallization with a suitable solvent, high performance liquid chromatography, column chromatography or gas chromatography.

Racemates of the compounds of general formula I can be cleaved by known methods, for example optically active acids such as (+) or (-) tartaric acid or (+) or (-) diacetyltartaric acid, (+) or It can be cleaved using its derivatives such as (−) monomethyl tartaric acid ester or (+) camphorsulphonic acid. According to the customary method of enantiomer separation, the racemate of the compound of general formula I is reacted in equimolar amounts with one of the abovementioned optically active acids in a solvent and the crystalline diastereomeric salt obtained is obtained. Are separated based on their different solubilities. This reaction can be carried out in any kind of solvent, provided that the solvents show sufficiently large differences in the solubility of the salts. Preference is given to using methanol, ethanol or mixtures thereof, for example mixtures in a volume ratio of 50:50. Each of the optically active salts is then dissolved in water and neutralized with a base such as sodium carbonate or potassium carbonate, thus giving the corresponding free compounds in the (+) or (−) form. A single enantiomer or a mixture of two optically active diastereomeric compounds of the general formula I is obtained when the above synthetic method is carried out with only the corresponding enantiomer. The starting compound of general formula II may be prepared as follows. For example, the general formula VI:

[0018]

[Chemical 11]

(Aminoalkyl) pyridines (wherein n and R ¹ are as defined above) (compounds of this type are known in the literature and in some cases also commercially obtainable) Can be tert. Butoxycarbonylated by known methods, thus giving the general formula VII:

[0020]

[Chemical formula 12]

To produce the compound of Catalytic hydrogenation of these compounds by known methods, for example hydrogenation using platinum (IV) oxide as a catalyst in ethanolic hydrochloric acid solution (F.
F. Blicke et al., J. Org. Chemistry 26: 3258 (1961)) or hydrogenation in the presence of platinum (IV) oxide in glacial acetic acid (WF Minor et al., J. Med. Pharm. Chem. : 96,105ff (196
2) and AH Sommers et al., J. Amer. Chem. Soc. 75: 57,58ff.
(See (1953)) has the general formula VIII:

[0022]

[Chemical 13]

This gives a compound of the general formula IX:

[0024]

[Chemical 14]

## STR1 ## where X, B and m are as defined above and Hal represents a chlorine atom, a bromine atom or an iodine atom.
This amination is carried out in an inert solvent at a temperature between -10 ° C and the boiling temperature of the solvent, preferably at least 2 mol of the general formula VIII.
With a secondary amine of 1 to 2 moles of the general formula VIII
Of secondary amine and auxiliary base. Examples of solvents are chlorinated aliphatic hydrocarbons such as methylene chloride, chloroform or dichloroethane; open chain ethers or cyclic ethers such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine. Alcohols such as ethanol or isopropanol; ketones such as acetone; acetonitrile, dimethylformamide or 1,3-dimethyl-2-imidazolidinone. Examples of auxiliary bases are tertiary organic bases,
For example triethylamine, N-methylpiperidine, diethylaniline, pyridine and 4- (dimethylamino) pyridine, or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides. If desired, the reaction can be accelerated by the addition of alkali metal iodide. Thus, the general formula X:

[0026]

[Chemical 15]

A compound of the formula ## STR6 ## in which the groups B, X, R ¹ and m and n are as defined above, is obtained, from which the tert.butoxycarbonyl group is known,
Cleavage, for example using hydrobromic acid in glacial acetic acid, thereby producing compounds of general formula II. The activated carboxylic acids of the formula III are conveniently obtained in the reaction mixture by methods known from the literature. Diazepinones of general formula IV are known from the literature (European patent application Nos. 39519 and 57).
No. 428, German Patent Nos. 1179943 and 1204680, F. Hunzicker et al., Arzneim.Forsch. 13: 324 (1963).
checking) . Carboxylic acid derivatives of the general formula V, in which Nu represents an alkoxy group, use a substituted piperidine of the general formula VIII, optionally with an additional auxiliary base, such as triethylamine, or a catalyst, such as Triton B. Then, it is obtained by reacting with a corresponding haloalkanoic acid ester. The resulting ester is saponified using, for example, a barium hydroxide solution to give a carboxylic acid of the general formula V (wherein Nu represents a hydroxy group). The carboxylic acid thus obtained can then be utilized as a starting material for the preparation of other nucleofugal group-containing derivatives, for example the acid halides of formula V. The invention further relates to pharmaceutical compositions comprising one or more fused diazepinones of general formula I or physiologically acceptable salts thereof. For this purpose, the compounds of the general formula I can be incorporated into the customary pharmaceutical preparations in known manner, for example solutions, suppositories, simple or coated tablets, capsules or infusion solutions. The daily dose should be adjusted to achieve the desired result.
Generally 0.02 to 5 mg / kg body weight, preferably 1 kg body weight
0.02-2.5mg / kg, more particularly 0.05-kg / kg
It is 1.0 mg, and is administered in the form of a single dose, if necessary, several times, preferably 1 to 3 times.

As mentioned above, the base-substituted fused diazepinones of general formula I and their acid addition salts possess valuable properties. Thus, they have an advantageous selectivity for the cardiac M ₂ receptor and therefore can be used as vagal pacemakers for treating bradycardia and bradyarrhythmias in both human and veterinary medicine. The fact that the muscarinic receptors in the basilar arteries responsible for vasoconstriction are of the M ₂ type is known from studies done by van Charldorp and van Zwieten (KJ van Charldorp, “Characterisation of Muscarinic Receptors”). in t
he Vascular System ", Amsterdam1988; KJvan Charldor
p.D.Davidesko and PAvan Zwieten, Eur.J.Pharmaco
l.150: 197-199 (1988); KJvan Charldorp and PAvan.
Zwieten, Naunyn Schmiedeberg's Arch. Pharmacol. 339: 4
03-408 (1989)). Therefore, M ₂ antagonists could be expected to relax cerebral blood vessels, thereby increasing blood flow. Thus, inhibition of detectable muscarinic receptors in cerebral blood vessels results in prevention of stenosis and amelioration or normalization of arteriosclerosis-induced disease of cerebral blood flow. The novel compounds of the invention are particularly suitable for ameliorating or normalizing arteriosclerosis-induced diseases of cerebral blood flow. Due to their high lipophilicity, some of the compounds of general formula I show good CNS efficacy and are therefore more suitable for the treatment of central nervous system diseases, in particular Alzheimer's disease. In senile dementia of the Alzheimer's type, degeneration of cholinergic neurons, especially in the hippocampus and cortical processes, results in a reduced release of the neurotransmitter acetylcholine. Then
Blockage of presynaptic autoreceptors disrupts the negative feedback mechanism, which neurotransmitters impart to still intact neurons, resulting in increased release of acetylcholine, resulting in postsynaptic receptors. (DCMash, DLFlynn and LTPo
tter, Science 228: 115-117 (1985); EKPerry et al., Can.J.
Neurol. Sci. 13: 521-527 (1986); M. Sarter et al., TINS 11: 13-.
17 (1988)). Therefore, these compounds are suitable for use in geriatrics and significantly improve learning and attention.

The following tests were performed to demonstrate the beneficial effects on cerebral blood flow. A. Studies on binding to muscarinic receptors Male Wistar rats (Chbb: THOM system, body weight 180
~ 220g) killed with a blow to the back of the neck. Cerebral cortex, heart and salivary glands were removed, washed and used in an Ultra-Turrax device at a maximum speed of 60 g rotation to obtain 20 volumes of HEPES buffer (20 mmol 4- (2-
Hydroxyethyl) -1-piperazino-ethanesulfonic acid, 100 mmol sodium chloride. Homogenized in 10 mmol magnesium chloride, pH 7.5). The homogenized material was diluted 1: 500 based on the original volume of tissue. For binding studies, 1 nM [ ³ H] pirenzepine (3.22 TBq / mmol) (which binds to the cortical M ₁ receptor) and 0.3 nM [ ³ H] NMS ( ³ to bind to the heart and salivary glands). HN-
Methylscopolamine) (2.64 TBq / mmol) at ambient temperature for 90 min for [ ³ H] pirenzepine and 40 min for [ ³ H] NMS, in each case 0.35 per 0.5 mL of heart, salivary gland and cortex samples. mg, 0.30 mg and 0.20 mg
Was incubated with the protein. The protein concentration was measured by the method of Lowry et al. (J. Biol. Chem. 93: 265). The incubation was terminated by high speed filtration through glass fiber filters using a Skatron Cell Harvester.
After washing twice (about 3 ml of liquid for 10 seconds), the filter is dried in air, filled into mini-vials, shaken overnight with 4 ml of scintillation liquid, and packed with Packard.
d) Scintillation was measured using a 460C instrument with an efficiency of 45-50%. All tests were done 3 times. Non-specific binding was defined as radioactivity in the presence of 1 μM of (−)-3-quinuclidinyl-benzylate. Computer-aided non-linear least-squares curve fitting method for binding data (G. Heinzel, “Pharmacokinetics durin
g Drug Development: Data Analysis and Evaluation Te
chniques ", G. Bozler and JM van Rossum (Gustav-Spri
Nger-Verlag), pp. 207, 1982).
The dissociation constant Ki was set to Cheny and Prusoff (Biochem.Pharmacol.
Calculated from IC ₅₀ values according to 2: 3099 (1973)). The results are shown in Table 1.

B. Central Activity Research Principles: Arecoline has both central and peripheral active ingredients. Peripheral (hypotensive) effects are blocked by N-methylscopolamine, resulting in only central (hypertensive) effects of arecoline. Brain-effective antimuscarinic substance
(antimuscarinics) block this central effect. Method : Male rats weighing 300 g were anesthetized intraperitoneally (ip) with urethane (1.2 g / kg). The trachea was incubated and the animals were breathed with an air / oxygen mixture (80 breaths per minute).
.. Blood pressure is recorded by a pressure recorder (Bell and Howell type 4-327-I) after carotid cannulation. Test substance administered via jugular vein (0.5
Mol / kg). Animals are given 0.5 mg / kg N-methyl-scopolamine prior to the start of the study. Arecoline is given at 15-minute intervals (dose of 0.3 mg / kg). After the two comparison values, the test substance is injected in increasing doses 5 minutes before the next administration of arecoline. The obtained results were compared with the average starting value and measured as the inhibition rate (%). Table 2 contains the values actually measured in the arecoline test.

C. Morris Mater Maze
Effects on memory in RMG Morris were tested using the water maze described by Learn Motive 12: 239-249 (1981) using the test method described therein. On the first day, rats 24 months old and thus impaired learning ability (n = 7 per group) were given compound D 0.2 mg / kg by subcutaneous route,
Meanwhile, saline (sc) to another group of these animals
Was given. These groups were observed in the Morris water maze for 4 days. As evidenced by the pathway of the curves shown in Figure 1, administration of Compound D impaired learning abilities due to age and resulted in improved memory performance compared to saline-treated animals. Bring Thus
For example, on day 2, the incubation period was reduced by about 50%. On day 4, animals treated with substance D were treated with a control group of young rats treated with saline alone (n per group).
= 7) reached the same level. This effect of the M ₂ antagonists of the invention is surprising. This is because a decrease in learning ability and memory ability was observed after administration of the M ₁ selective antagonist pirenzepine (AJ Hunter and FF Robert).
s, Pharmacol. Biochem. and Behavior Vol. 30, 519-523 (198
8), titled “The effects of pirenzepin on spatial le
arning in the Morris Water Maze "). Similar negative observations after administration of non-selective substances such as scopolamine or atropine were also found by AJ Hunter, FF Roberts and CA Cutty.
Wr. J. Pharmacol. 87: 41P (1986); RJ Sutherland, I.
Q. Wishaw and JC Regehr, J.Comp.Physiol.Psychol.9
6: 563-573 (1982) and IQ Wishaw, Behav. Neurosc.
i.99: 979-1005 (1985).

The following compounds were investigated using the above method, for example: A = 5,11-dihydro-11-[[4-
[3-[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, B = 5,11-dihydro-[[4-
[3-[(2,2-dimethyl-1-oxopentyl)-
Ethylamino] -propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, C = 5,11-dihydro-11-
[[4- [4-[(2,2-Dimethyl-1-oxopentyl) -ethylamino] butyl] -1-piperidinyl]
Acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, D = 5,11-dihydro-8
-Chloro-11-[[4- [3-[(2,2-dimethyl-
1-oxopentyl) -ethylamino] propyl] -1
-Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one, E = 5
11-dihydro-8-methyl-11-[[4- [3-
[(2,2-Dimethyl-1-oxopropyl) -ethylamino] propyl] -1-piperidinyl] acetyl]-
6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, F = 5,11-dihydro-11-[[4-
[3-[(2,2-dimethyl-1-oxopropyl)-
Ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one G = 5,11-dihydro-8-methyl-11-[[4 -[3
-[(2,2-Dimethyl-1-oxobutyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one.

These compounds were compared with the following known substances. H = 11-[[2-[(diethylamino) methyl]-
1-piperidinyl] acetyl] -5,11-dihydro-6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (see U.S. Pat. No. 4,550,107) I = 11-[[4- [4- (diethylamino) butyl]-
1-piperidinyl] acetyl] -5,11-dihydro-6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (see European Patent Application No. 312895) From European Patent Application No. 402734, J = 5,11-dihydro-
11- [1-oxo-6- (1-piperidinyl) -4-hexyn-1-yl] -6H-pyrido [2,3-b]
[1,4] Benzodiazepin-6-one K = (±) -9-chloro-11-[[2-[(diethylamino) methyl] -1-piperidinyl] -acetyl]-
5,11-Dihydro-6H-pyrido [2,3-b] [1,
4] benzodiazepin-6-one L = 5,11-dihydro-11-[[[2- [2-[(dipropylamino) methyl] -1-piperidinyl] ethyl]
Amino] carbonyl] -6H-pyrido [2,3-b]
[1,4] benzodiazepin-6-one methanesulfonate M = 5,11-dihydro-11-[[3- [3- (1-piperidinyl) -1-propyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one N = 4,9-dihydro-3-methyl-4-[[4- [3
-(1-Piperidinyl) -1-propyl] -1-piperidinyl] acetyl] -10H-thieno [3,4-b]
[1,5] benzodiazepin-10-one O = 5,11-dihydro-11- [1-oxo-6- (1-
Piperidinyl) -1-hexyl] -6H-pyrido [2,2
3-b] [1,4] benzodiazepin-10-one P =
4,9-Dihydro-3-methyl-4- [6- (hexahydro-1H-1-azepinyl) -1-oxo-4-hexyn-1-yl] -10H-thieno [3,4-b] [1 ，
5] Benzodiazepin-10-one Q = 11- [4- [3-[(diethylamino) methyl]-
4-morpholinyl] -1-oxo-1-butyl] -5,
11-dihydro-6H-pyrido [2,3-b] [1,4]
Benzodiazepin-6-one R = 5,11-dihydro-11-[[[2- (1-methyl-
2-Pyrrolidinyl) -ethyl] -methylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one S = 5,11-dihydro-11-[[[2- ( 1-methyl-
Hexahydro-1H-2-azepinyl) -ethyl] methylamino] acetyl] -6H-pyrido [2,3-b]
[1,4] benzodiazepin-6-one.

The results are shown in Tables 1 and 2 below.

[0035]

[Table 1]

[0036]

[Table 2] CNS penetrant in vivo (rat) ED ₅₀ [mg / kg] decrease in blood pressure-induced increase in arecoline A 4.5 B 1.3 C 2.0 D 5.0 E 2.8 F 6.5 G 5.1 H> 10.0 K> 10.0 L> 10.0 O> 10.0

As shown in Table 1, specific compounds A to
G exhibits excellent M ₁ / M ₂ selectivity in the range 10-35. This ratio indicates that certain compounds are highly selective and therefore M
_{It is shown that 1} receptor can block the presynaptic M ₂ receptor in the brain at an unaffected dose. In contrast, the comparative substances H to S show only modest M ₁ / M ₂ selectivity with a selectivity ratio of less than 6.6. Comparison of these selectivity values shows that the novel diazepinones of general formula I are far superior to the comparison substances. An essential prerequisite for the suitability of compounds for treating CNS disorders is the brain efficacy of these substances. The above test model to demonstrate CNS penetration clearly shows that substances AG can suppress arecoline mediated central effects (see Table 2). This finding can be explained solely on the basis of good CNS efficacy. In contrast, the tested comparative substances H, K, L and O with an ED ₅₀ value (intravenous dose, iv) greater than 10 mg / kg had no effect on the increase in blood pressure caused by arecoline. This clearly shows that these compounds have a rather poor penetration into the central nervous system. The following examples are intended to illustrate the invention.

[0038]

EXAMPLE 1 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxobutyl) -ethylamino] -propyl] -1-piperidinyl] acetyl] -6H -Pyrid
[2,3-b] [1,4] benzodiazepin-6-one 1.48 g (0.01 mol) of 2,2-dimethylbutyric acid chloride dissolved in 20 ml of tetrahydrofuran were stirred at ambient temperature while stirring at 5,11 in 5,11 of tetrahydrofuran. -Dihydro-11-
[[4- [3- (Ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b]
It is added dropwise to a solution of 4.2 g (0.01 mol) of [1,4] benzodiazepin-6-one and 2 ml of triethylamine. The solution is stirred at 50 ° C. for a further hour to complete the reaction. After cooling, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness under reduced pressure with a water jet pump using a rotary evaporator. The residue is dissolved in ethyl acetate in order to purify it. The ethyl acetate solution is extracted twice with 10% hydrochloric acid, the organic phase is separated off and the aqueous phase is made alkaline by addition of concentrated ammonia. The aqueous phase is then extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated to dryness under reduced pressure. It is crystallized by digesting the residue obtained in ethyl acetate. Colorless crystals with a melting point of 136-138 ° C. are obtained. Yield: 2.4 g (46.2% of theory). Example 2 5,11-Dihydro-11-[[4- [3-[(benzoyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4 ] Ben
Zodiazepin-6-one dihydrochloride 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and benzoic acid chloride. The free base is dissolved in ethyl acetate and the dihydrochloride salt is precipitated by addition of ethereal hydrochloric acid. The desired compound is obtained by recrystallization with ethanol in a yield of 62%. Colorless crystals with a melting point of 152-154 ° C (recrystallized from ethanol).

Example 3 5,11-Dihydro-11-[[4- [3-[(4-methoxybenzoyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3- b ] ]
[1,4] Benzodiazepin-6-one dihydrochloride 5,11-Dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and 4-methoxybenzoic acid chloride. The free base is dissolved in ethyl acetate and the dihydrochloride salt is precipitated by addition of ethereal hydrochloric acid. 81 recrystallization of the desired compound with ethanol
Obtained in% yield. Colorless crystals with a melting point of 163-165 ° C (recrystallized from ethanol). Example 4 5,11-Dihydro-11-[[4- [3-[(3,4-dimethoxybenzoyl) ethylamino] -propyl] -1
-Piperidinyl] acetyl] -6H-pyrido [ 2,3-
b] [1,4] Benzodiazepin-6-one dihydrochloride 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and 3,4-dimethoxybenzoic acid chloride. The free base is dissolved in ethyl acetate and the dihydrochloride salt is precipitated by addition of ethereal hydrochloric acid. Yield: 78% of theory Colorless crystals with a melting point of 160-162 ° C (recrystallized from ethanol). Example 5 5,11-Dihydro-11-[[4- [3-[(phenylacetyl) ethylamino] -propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Benzodiazepin-6-one dihydrochloride 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and phenylacetyl chloride. The free base was purified by chromatography on silica gel (Merck, 30-60 μm) using a mixture of ethyl acetate / methanol (98: 2) as eluent, then treated with ethereal hydrochloric acid to give dihydrochloride. Convert to salt. Yield: 24% of theory, colorless crystals with a melting point of 149-152 ° C (recrystallized from ethanol).

Example 6 5,11-Dihydro-11-[[4- [3-[(acetyl))
Ethylamino ] propyl] -1-piperidinyl] acetyl] -6H -pyrido [2,3-b] [1,4] benzodi
Azepin- 6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and acetyl chloride in a yield of 56% of theory. Colorless crystals with a melting point of 178-180 ° C (recrystallized from ethyl acetate). Example 7 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxo-propyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H- pyrido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and pivaloyl chloride in a yield of 61% of theory. Colorless crystals with a melting point of 154-155 ° C (recrystallized from ethyl acetate). Example 8 5,11-Dihydro-11-[[2- [2-[(benzoyl) methylamino] ethyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] Benzo
Diazepin-6-one 11- (chloroacetyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-
On 9.5 g (0.033 mol), 2- [2-[(benzoyl) methylamino] ethyl] -piperidine 9.8 g (0.04 mol),
Sodium carbonate 4.2 g (0.04 mol) and acetonitrile 30
Reflux 0 ml of the mixture for 10 hours. Then the reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The crude product thus obtained was eluted with methylene chloride / methanol / cyclohexane / ammonia / ethyl acetate = 68: 15: 15: 2: 50
Silica gel (Baker, 30-60 μ
Purify by chromatography according to m). Colorless crystals with a melting point of 115-130 ° C. Yield: 3.8g (25% of theory)

Example 9 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pi Lido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and 2,2-dimethylvaleric acid chloride in a yield of 62% of theory. Colorless crystals with a melting point of 138-140 ° C (recrystallized with diethyl ether). Example 10 5,11-Dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxopropyl) ethylamino] propyl] -1-piperidinyl] acetyl ] -6
H-pyrido [2,3-b] [1,4] benzodiazepines
-6-one 5,11-dihydro-8-chloro-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] Prepared from [1,4] benzodiazepin-6-one and pivaloyl chloride in a yield of 77% of theory. Colorless crystals with a melting point of 168-170 ° C (recrystallized with ethyl acetate). Example 11 5,11-Dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl ] -6
H-pyrido [2,3-b] [1,4] benzodiazepines
-6-one 5,11-dihydro-8-chloro-in the same manner as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylbutyric acid chloride in a yield of 36% of theory. Melting point 173-174 ° C (recrystallized with diisopropyl ether)
Colorless crystals of.

Example 12 5,11-dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxopentyl) -ethylamino] propyl] -1-piperidinyl] acetyl ]-
6H-pyrido [2,3-b] [1,4] benzodiazepi
N-6-one 5,11-dihydro-8-chloro-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylvaleric acid chloride in 70% of theory yield. Colorless crystals, melting point 172-173 ° C (recrystallized from ethyl acetate). Example 13 5,11-Dihydro-8-chloro-11-[[4- [3-
[(Cyclopropylcarbonyl) -ethylamino] propyl] -1-piperidinyl] acetyl] -6H- pyrido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-8-chloro-as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
Prepared from b] [1,4] benzodiazepin-6-one and cyclopropanecarboxylic acid chloride in a yield of 76% of theory. Colorless crystals with a melting point of 136-138 ° C (recrystallized from diethyl ether / ethyl acetate). Example 14 5,11-Dihydro-8-methyl-11-[[4- [3-
[(2,2-dimethyl-1-oxopropyl) - ethylamino] propyl] -1-piperidinyl] acetyl Le -
6H-pyrido [2,3-b] [1,4] benzodiazepi
N-6-one 5,11-dihydro-8-methyl-as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
Prepared from b] [1,4] benzodiazepin-6-one and pivaloyl chloride in a yield of 23% of theory. Colorless crystals, melting point 177-179 ° C (recrystallized from acetonitrile).

Example 15 5,11-Dihydro-9-chloro-11-[[4- [3-
[(2,2-dimethyl-1-oxopentyl) - ethylamino] propyl] -1-piperidinyl] acetyl Le -
6H-pyrido [2,3-b] [1,4] benzodiazepi
N-6-one 5,11-dihydro-9-chloro-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylvaleric acid chloride. Purification was carried out by chromatography on silica gel (Merck, 30-60 μm) using a mixture of ethyl acetate / ammonia (10: 0.1) as eluent. Yield: 48% of theory, colorless crystals with a melting point of 150-152 ° C (recrystallized from diethyl ether). Example 16 5,11-Dihydro-9-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl ] -6
H-pyrido [2,3-b] [1,4] benzodiazepines
-6-one 5,11-dihydro-9-chloro-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylbutyric acid chloride. The base was purified by chromatography on silica gel (Merck, 30-60 μm) using a mixture of ethyl acetate / ammonia (10: 0.1). Yield: 54% of theory, colorless crystals, mp 123-125 ° C (recrystallized with diethyl ether). Example 17 5,11-Dihydro-8-methyl-11-[[4- [3-
[(2,2-Dimethyl-1-oxobutyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H
-Pyrido [2,3-b] [1,4] benzodiazepine-
6-one 5,11-dihydro-8-methyl-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylbutyric acid chloride. Purification was carried out by chromatography on silica gel (Baker, 30-60 μm) using a mixture of ethyl acetate / ammonia (10: 0.1) as eluent. Yield: 41% of theory, colorless crystals with a melting point of 97-99 ° C (recrystallized with ethyl acetate).

Example 18 5,11-Dihydro-8-methyl-11-[[4- [3-
[(2,2-Dimethyl-1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl ] -6
H-pyrido [2,3-b] [1,4] benzodiazepines
-6-one 5,11-dihydro-8-methyl-as in Example 1
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] benzodiazepin-6-one and 2,2-
Prepared from dimethylvaleric acid chloride. Purification was carried out by chromatography on silica gel (Baker, 30-60 μm) using a mixture of ethyl acetate / ammonia (10: 0.1) as eluent. Yield: 28% of theory, colorless crystals with a melting point of 83-85 ° C (recrystallized with ethyl acetate). Example 19 5,11-Dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxo-4-pentene-1
-Yl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Benzodiazepin -6-one 2,2-dimethyl-4-pentenoic acid chloride and 5,11-dihydro-8-chloro-11-as described in Example 1.
[[4- [3- (Ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b]
Prepared from [1,4] benzodiazepin-6-one.
Silica gel using a mixture of ethyl acetate / methanol / cyclohexane / ammonia = 8: 1: 1: 0.1 as eluent
Purification was performed by chromatography (Baker, 30-60 μm). Yield: 88% of theory, colorless crystals, mp 157-158 ° C (recrystallized from diethyl ether).

Example 20 5,11-Dihydro-8-chloro-11-[[4- [3-
[(Cyclohexylcarbonyl) -ethylamino] propyl] -1-piperidinyl] acetyl] -6H- pyrido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-8-chloro-as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] Prepared from [1,4] benzodiazepin-6-one and cyclohexanecarboxylic acid chloride. Ethyl acetate / methanol / cyclohexane / ammonia as eluent
Purification was carried out by chromatography on silica gel (Baker, 30-60 μm) using the mixture = 8: 1: 1: 0.1. Yield: 70% of theory, colorless crystals, mp 162-163 ° C (recrystallized with diethyl ether). Example 21 5,11-Dihydro-8-chloro-11-[[4- [3-
[(1-oxopentyl) ethylamino] propyl]-
1-piperidinyl] acetyl] -6H-pyrido [ 2,3
-B ] [1,4] benzodiazepin-6-one 5,11-dihydro-8-chloro-as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] Benzodiazepin-6-one prepared from valeric acid chloride. Purification was carried out by chromatography on silica gel (Baker, 30-60 μm) using a mixture of ethyl acetate / methanol / cyclohexane / ammonia = 8: 1: 1: 0.1 as eluent. Yield: 73% of theory, colorless crystals with a melting point of 150-152 ° C (recrystallized from diethyl ether).

Example 22 5,11-Dihydro-8-chloro-11-[[4- [3-
[(1-Oxobutyl) ethylamino] propyl] -1
- piperidinyl] acetyl]-6H-pyrido [2, 3-
b] [1,4] Benzodiazepin-6-one 5,11-dihydro-8-chloro-in analogy to Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] Benzodiazepin-6-one and butyric acid chloride. Purification by chromatography on silica gel as in Example 21. Yield: 75% of theory Colorless crystals with a melting point of 152-154 ° C (recrystallized from diethyl ether). Example 23 5,11-dihydro-8-chloro-11-[[4- [3-
[(1-oxopropyl) ethylamino] propyl]-
1-piperidinyl] acetyl] -6H-pyrido [ 2,3
-B ] [1,4] benzodiazepin-6-one 5,11-dihydro-8-chloro-as in Example 1.
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
b] [1,4] Prepared from benzodiazepin-6-one and propionic acid chloride. Purification by chromatography on silica gel as in Example 21. Yield: 77% of theory, colorless crystals with a melting point of 141-143 ° C (recrystallized from diethyl ether). Example 24 5,11-Dihydro-11-[[4- [3-[(1-oxopropyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1 ，
4] Benzodiazepin-6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and propionyl chloride. Purification by chromatography on silica gel as in Example 21. Yield: 50% of theory, colorless crystals, mp 123-125 ° C (recrystallized with diethyl ether).

Example 25 5,11-Dihydro-11-[[4- [3-[(1-oxobutyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [ 1,
4] Benzodiazepin-6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and butyric acid chloride. Purification by chromatography on silica gel as in Example 21. Yield: 61% of theory, colorless crystals with a melting point of 174-175 ° C (recrystallized from diethyl ether). Example 26 5,11-Dihydro-11-[[4- [3-[(1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1 ，
4] Benzodiazepin-6-one 5,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] Prepared from benzodiazepin-6-one and valeric acid chloride. Purification by chromatography on silica gel as in Example 21. Yield: 64% of theory, colorless crystals with a melting point of 167-168 ° C (recrystallized from diethyl ether).

Example 27 5,11-Dihydro-8-chloro-11-[[4- [3-
[(1-Methylcyclohexylcarbonyl) ethylamino] propyl-1-piperidinyl] acetyl] -6H-
Pyrido [2,3-b] [1,4] benzodiazepine-6
A solution of 313 mg (2.2 mmol) 1-methylcyclohexanecarboxylic acid and 340 mg (3.0 mmol) N, N'-carbonyldiimidazole in 20 ml of 1- on tetrahydrofuran is heated to 45 ° C. for 1 hour with stirring. Then 5,11-dihydro-8-chloro-[[4- [3-[(ethylamino)-
Propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-
920 mg (2 mmol) of ON was added and the reaction mixture was added to 45
Stir for an additional 2 hours at ° C. After the reaction is complete, the reaction mixture is poured into saturated sodium chloride solution, the organic phase is separated off,
Evaporate and dry under reduced pressure. The residue obtained is partitioned between water and ethyl acetate, then the ethyl acetate phase is evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel (Baker, 30-60 μm) using a mixture of ethyl acetate / methanol / ammonia (9: 1: 0.1).
). Yield 130 mg (theoretical) of the desired compound.
11%) as an amorphous product. R _f value of thin layer chromatogram: 0.4 (TLC plate: silica gel made by Merck & Co .; eluent: methylene chloride / cyclohexane / methanol / ammonia = 680: 15
0: 150: 20). Example 28 5,11-Dihydro-8-chloro-11-[[4- [3-
[(Tricyclo [3,3,1,1 ^3,7 ] decyl-1-carbonyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,
4] benzodiazepines 6-one Example 1 in analogy to 5,11-dihydro-8-chloro -
11-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -6H-pyrido [2,3-
Prepared from b] [1,4] benzodiazepin-6-one and tricyclo [3,3,1,1 ^3,7 ] decane-1-carboxylic acid chloride in a yield of 20% of theory. Ethyl acetate / cyclohexane / methanol / ammonia as eluent
Purification by chromatography on silica gel (Baker) using a mixture of = 80: 10: 10: 1. R _f value of thin layer chromatogram: 0.65 (TLC plate: silica gel produced by Merck & Co .; eluent: methylene chloride / cyclohexane / methanol / ammonia = 680: 15
0: 150: 20).

Example 29 5,11-Dihydro-11-[[4- [4-[(2,2-dimethyl-1-oxopropyl) -ethylamino] butyl] -1-piperidinyl] acetyl] -6H- Rain Lido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[4- (ethylamino) butyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and pivaloyl chloride in a yield of 62% of theory. Colorless crystals with a melting point of 206-207 ° C (recrystallized with ethyl acetate). Example 30 5,11-Dihydro-11-[[4- [4-[(cyclopropylcarbonyl) -ethylamino] butyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3- b]
[1,4] Benzodiazepin-6-one 5,11-dihydro-11-[[4-
[4- (ethylamino) butyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and cyclopropanecarboxylic acid chloride in 67% yield of theory. Colorless crystals with a melting point of 202-204 ° C (recrystallized with ethyl acetate). Example 31 5,11-Dihydro-11-[[4- [4-[(2,2-dimethyl-1-oxobutyl) -ethylamino] butyl]
-1-piperidinyl] acetyl]-6H-pyrido [2,
3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[4- (ethylamino) butyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 2,2-dimethylbutyric acid chloride in a yield of 64% of theory. Colorless crystals with a melting point of 153-155 ° C (recrystallized from diethyl ether).

Example 32 5,11-Dihydro-11-[[4- [4-[(2,2-dimethyl-1-oxopentyl) -ethylamino] butyl] -1-piperidinyl] acetyl] -6H- Rain Lido
[2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[4- (ethylamino) butyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 2,2-dimethylvaleric acid chloride in 69% yield of theory. Colorless crystals with a melting point of 168-169 ° C (recrystallized from ethyl acetate). Example 33 5,11-Dihydro-11-[[4- [4-[(3,4-dimethoxybenzoyl) -ethylamino] butyl] -1-
Piperidinyl] acetyl]-6H-pyrido [2, 3-
b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
[4- (ethylamino) butyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 3,4-dimethoxybenzoic acid chloride in 67% yield of theory. Colorless crystals with a melting point of 132-135 ° C. (recrystallized with ethyl acetate). Example 34 5,11-dihydro-8-chloro-11-[[4- [4-
[(2,2-Dimethyl-1-oxopropyl) ethylamino] butyl] -1-piperidinyl] acetyl] -6H
-Pyrido [2,3-b] [1,4] benzodiazepine-
6-one 5,11-dihydro-8-chloro-as in Example 1
11-[[4- [4- (Ethylamino) butyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b]
Prepared from [1,4] benzodiazepin-6-one and pivaloyl chloride in a yield of 55% of theory. Colorless crystals with a melting point of 205-207 ° C (recrystallized from ethyl acetate).

Example 35 5,11-Dihydro-8-chloro-11-[[4- [4-
[(2,2-Dimethyl-1-oxopentyl) ethylamino] butyl] -1-piperidinyl] acetyl] -6H
-Pyrido [2,3-b] [1,4] benzodiazepine-
6-one 5,11-dihydro-8-chloro-as in Example 1
11-[[4- [4- (Ethylamino) butyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b]
Prepared from [1,4] benzodiazepin-6-one and 2,2-dimethylvaleric acid chloride in a yield of 60% of theory. Colorless crystals with a melting point of 149-151 ° C (recrystallized from ethyl acetate). Example 36 4,9-Dihydro-3-methyl-4-[[4- [3-
[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl ] -10
H-thieno [3,4-b] [1,5] benzodiazepines
-10-one 4,9-dihydro-3-methyl-in the same manner as in Example 1.
4-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -10H-thieno [3,4-
b] [1,5] benzodiazepin-10-one and 2,2-
Prepared from dimethylbutyric acid chloride in a yield of 19% of theory. Colorless crystals with a melting point of 207-208 ° C (recrystallized from acetonitrile). Example 37 4,9-Dihydro-3-methyl-4-[[4- [3-
[(2,2-dimethyl-1-oxopropyl) - ethylamino] propyl] -1-piperidinyl] acetyl Le -
10H-thieno [3,4-b] [1,5] benzodiazepi
N-10-one 4,9-dihydro-3-methyl-as in Example 1
4-[[4- [3- (ethylamino) propyl] -1-
Piperidinyl] acetyl] -10H-thieno [3,4-
b] Prepared from [1,5] benzodiazepin-10-one and pivaloyl chloride in a yield of 29% of theory. Colorless crystals, melting point 188-189 ° C (recrystallized from acetonitrile).

Example 38 5,11-Dihydro-11-[[4- [2-[(benzoyl) methylamino] ethyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1 , 4] Benzo
Diazepin- 6-one 5,11-dihydro-11-[[4-
[2- (methylamino) ethyl] -1-piperidinyl]
Prepared from acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and benzoyl chloride in 80% yield of theory. Colorless crystals with a melting point of 120-122 ° C (recrystallized with ethyl acetate). Example 39 5,11-Dihydro-11-[[4-[[(acetyl) methylamino] methyl] -1-piperidinyl] acetyl]-
6H- pyrido [2,3-b] [1,4] benzo Jiazepi
N-6- one In analogy to Example 1, 5,11-dihydro-11-[[4-
83% of theory from [(methylamino) methyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and acetyl chloride
Was prepared in a yield of Colorless crystals, melting point 242-243 ° C (recrystallized from ethyl acetate). Example 40 3-Chloro-4-[[4- [3-[(2,2-dimethyl-1-oxopropyl) ethylamino] propyl] -1
-Piperidinyl] acetyl] -1-methyl-1,4
9,10-Tetrahydropyrrolo [3,2-b] [1,5]
Benzodiazepin- 10- one In the same manner as in Example 1, 3-chloro-4-[[4- [3-
(Ethylamino) propyl] -1-piperidinyl] acetyl] -1-methyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine-10-
Prepared from on and pivalic acid chloride in 42% of theory yield. Colorless crystals with a melting point of 150-151 ° C (recrystallized with ethyl acetate).

Example 41 6,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl] -5H-pi Lido
[2,3-b] [1,5] benzodiazepin-5-one 6,11-dihydro-11-[[4-
[3- (ethylamino) propyl] -1-piperidinyl] acetyl] -5H-pyrido [2,3-b] [1,
5] Prepared from benzodiazepin-5-one and 2,2-dimethylvaleric acid chloride in a yield of 44% of theory. R _f value of thin layer chromatogram: 0.6 (TLC plate: silica gel made by Merck; eluent: methylene chloride / cyclohexane / methanol / ammonia = 6.8: 1.
5: 1.5: 0.2). Example 42 5,11-Dihydro-8-chloro-11-[[4- [3-
[(2,2-dimethyl-1-oxopentyl) - ethylamino] propyl] -1-piperidinyl] acetyl Le -
6H-pyrido [2,3-b] [1,4] benzodiazepi
2,2-Dimethylvaleric acid in 50 ml of N-6-one tetrahydrofuran.
To a solution of 52 g (4 mmol) and 0.54 g of 1-hydroxybenzotriazole (4 mmol) is added 0.82 g (4 mmol) of N, N'-dicyclohexylcarbodiimide with stirring at 0 ° C. The mixture is stirred at the same temperature for a further 30 minutes and then 5,11-dihydro-8-chloro-11-
[[4- [3-[(Ethylamino) propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b]
1.8 g (4 mmol) of [1,4] benzodiazepin-6-one are added. The mixture is stirred at ambient temperature for a further 12 hours. The dicyclohexylurea formed is removed by suction filtration and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (Baker) using a mixture of ethyl acetate / methanol / cyclohexane / ammonia = 8: 1: 1: 0.1 as eluent.
Colorless crystals with a melting point of 172-173 ° C. (recrystallized with ethyl acetate) are obtained. Yield: 160 mg = 7% of theory. According to its physicochemical and spectroscopic data, the substance is
It is completely the same as the substance obtained by.

Example 43 5,11-Dihydro-11-[[3- [3-[(benzoyl) methylamino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1 , 4 ] Ben
Zodiazepin-6-one 11- (chloroacetyl) -5,11 as in Example 8.
Prepared from -dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 3- [3-[(benzoyl) methylamino] propyl] piperidine. Purification is carried out by chromatography on silica gel using a mixture of methylene chloride / methanol = 99: 1 as eluent. Yield: 43% of theory, colorless crystals with a melting point of 172-173 ° C. Example 44 5,11-Dihydro-11-[[3- [3-[(acetyl))
Methylamino] propyl] -1-piperidinyl] acetyl] -6H -pyrido [2,3-b] [1,4] benzodi
Azepin-6-one 11- (chloroacetyl) -5,11 as in Example 8
-Dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 3- [3-[(acetyl)
Prepared from methylamino] propyl] piperidine. Purification is carried out by chromatography on silica gel (Baker) using methylene chloride with the addition of increasing amounts of methanol as eluent. Yield: 23% of theory, colorless crystals with a melting point of 170-172 ° C. Example 45 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxopentyl) amino] propyl] -1
-Piperidinyl] acetyl] -6H-pyrido [ 2,3-
b] [1,4] benzodiazepin-6-one 5,11-dihydro-11-[[4-
From (3-aminopropyl) -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 2,2-dimethylvaleric acid chloride, 64% of the theoretical value was obtained. Prepared in yield. Colorless crystals with a melting point of 150-152 ° C (recrystallized with ethyl acetate)
..

Example 46 5,10-Dihydro-5-[[4- [3-[(2,2-dimethyl-1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl] -11H-di Benzo
[B, e] [1,4] diazepin-11-one 5,10-dihydro-5-[[4-
(3-Ethylamino] propyl] -1-piperidinyl]
Prepared from acetyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one. Silica gel using ethyl acetate / ammonia (10: 0.1) mixture as eluent
Purification is carried out by chromatography (Merck, 30-60 μm). Yield: 53% of theory, colorless crystals with a melting point of 124-126 ° C. (recrystallized with diethyl ether). R _f value of thin layer chromatogram: 0.5 (TLC plate: silica gel made by Merck; eluent: methylene chloride / cyclohexane / methanol / ammonia = 6.8: 1.
5: 1.5: 0.2).

The following examples show the preparation of several pharmaceutical dosage forms. Example I 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxobutyl) ethylamino] propyl]
-1-piperidinyl] acetyl]-6H-pyrido [2,
3-b] [1,4] benzodiazepin-6-one 5 mg
Tablet Composition Including : One tablet contains the following ingredients. Method of Preparation Prepared by heating 10% mucilage from potato starch. The active substance, lactose and the remaining potato starch are mixed together and granulated with the above-mentioned mucilage through a 1.5 mm mesh screen. The granules are dried at 45 ° C., rubbed on the screen again, mixed with magnesium stearate and compressed to form tablets. Tablet weight: 220 mg Punch: 9 mm. Example II 5,11-Dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxobutyl) ethylamino] propyl]
-1-piperidinyl] acetyl]-6H-pyrido [2,
3-b] [1,4] benzodiazepin-6-one 5 mg
Coated Tablets Containing The tablets prepared according to Example I are coated with a coating consisting essentially of sugar and talc by known methods. Polish the finish coated tablets with beeswax. Weight of coated tablet: 300 mg. Example III 5,11-Dihydro-11-[[4- [4-[(2,2-dimethyl-1-oxopentyl) ethylamino] butyl]
-1-Piperidinyl] acetyl] -6H-pyrido [2,2
3-b] [1,4] A sample composition comprising a benzodiazepine-6-one dihydrochloride 10 mg: 1 single ampoule contains the following components. Active substance 10.0 mg Sodium chloride 8.0 mg Distilled water 1 ml Amount preparation method The active substance and sodium chloride are dissolved in distilled water and then brought to the specified volume. The solution is sterile filtered and transferred to a 1 ml ampoule. Sterilization: 120 ° C for 20 minutes.

Example IV 5,11-Dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxo-pentyl) ethylamino] propyl] -1-piperidinyl] acetyl]-
Suppository composition containing 20 mg of 6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one: One suppository contains the following ingredients. Active substance 20.0 mg Suppository substance (eg Witepsol W45 ™) 1680.0 mg 1700.0 mg Method of preparation A finely divided active substance is suspended in a molten suppository substance cooled to 40 ° C. The material is poured at 37 ° C into a slightly cooled suppository mold. Suppository weight 1.7g. Example V 5,11-Dihydro-11 - [[4- [4 - [(2,2-dimethyl-1-oxo - pentyl) ethylamino] butyl] -1-piperidinyl] acetyl]-6H-pin Lido
[2,3-b] [1,4] benzodiazepin-6-one
Drop composition containing : 100 ml of the drop solution contains the following components. Methyl p-hydroxybenzoate 0.035 g Propyl p-hydroxybenzoate 0.015 g Anise oil 0.05 g Menthol 0.06 g Pure ethanol 10.0 g Active substance 0.5 g Sodium cyclamate 1.0 g Glycerol 15.0 g Distilled water 100 ml Preparation method Active substance and Dissolve sodium cyclamate in about 70 ml of water and add glycerol. p-Hydroxybenzoate, anise oil and menthol are dissolved in ethanol and this solution is added to the aqueous solution with stirring. Finally, the solution is made up to 100 ml with water and filtered to remove suspended particles.

[0058]

[Brief description of drawings]

FIG. 1 is a graph showing the results observed in rats administered the compound of the present invention in the Morris water maze test.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area C07D 471/04 121 8415-4C 471/14 102 8415-4C 487/04 152 7019-4C 495/04 108 7329-4C 495/14 E 7329-4C (72) Inventor Wolfhard Engel Federal Republic of Germany Vewe 7950 Viveratha 1 Mozartshutlerse 13 (72) Inventor Klaus Rudolf German Vue 7950 Viveratha 1 Marktplatz 38 (72) Inventor Henry Dautz, Germany Vue 7951 Värthausen Hornschütänwejk 7 (72) Inventor Härart Ziegler, Federal Republic of Germany Vue 7950 Viveratha 1 Ginsütelhalde 5 (72) Inventor Mihae Entsueroto Federal Republic of Germany Vue 7951 Vuaruto Oberhausen Sebasuchiyan Sailer Shiyu Torase 20

Claims (9)

[Claims] 1. Fused diazepinones of the general formula I and their salts with inorganic or organic acids. [Chemical 1] (In the formula, B represents one of the divalent groups represented by the following formula, and And X, 1, m, n and R ^{1 to} R ⁷ are as defined below, X is a ═CH— group, or when B represents a divalent group (S), X is May also represent a nitrogen atom, l represents the number 1, 2 or 3, m represents the number 1 or 2, n represents the number 1, 2, 3 or 4, R ¹ represents a hydrogen atom or a direct atom Represents a chain or branched C _1-6 alkyl group, R ² represents a hydrogen atom; a linear or branched C _1-8 alkyl group;
Linear or branched C _4-6 alkenyl; C as required
Optionally substituted by _1-3 alkyl groups C _{3- 7} cycloalkyl group; an adamantyl group; required by one or two methyl groups or methoxy group or a phenyl group optionally substituted by a halogen atom; or Represents a phenylalkyl group having 1 to 3 carbon atoms in the alkylene moiety optionally substituted by a methyl group or a methoxy group or a halogen atom with an aromatic group, and R ³ and R ⁴ are the same. ^{May be} different from each other, and may represent a hydrogen atom or a halogen atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, R ⁵ represents a hydrogen atom, a chlorine atom or a methyl group, and R ⁶ and R ⁷ May be the same or different and represent a hydrogen atom or a C _1-3 alkyl group,
R ⁷ may further represent a halogen atom). 2. X is a nitrogen atom, B is a divalent group (S), l is the number 2, m is the number 1, n is the number 3 or 4, and R ¹ is Is a straight-chain C _1-4 alkyl group, and R ² is a branched C _4-6 alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, methylcyclopentyl group, methylcyclohexyl group, methylcycloheptyl A group or an adamantyl group, R ³ and R ⁴ represent a hydrogen atom, or one of these groups represents a methyl group or a halogen atom, and the substituent — (CH ₂ ) _n —NR ¹ —CO— R ² is A fused diazepinone of the general formula I according to claim 1 attached to the 4-position of the piperidinyl ring and salts thereof with inorganic or organic acids. 3. A fused diazepinone of the general formula I according to claim 2 in which R ¹ represents an ethyl group and salts thereof with inorganic or organic acids. 4. 5,11-Dihydro-11-[[4- [3-
[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl] -6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 5,11-dihydro-[[4- [3-[(2,2-dimethyl-1-oxopentyl) -ethylamino ] Propyl]
-1-Piperidinyl] acetyl] -6H-pyrido [2,2
3-b] [1,4] benzodiazepin-6-one, 5,11-dihydro-11-[[4- [4-[(2,2-dimethyl-1-oxopentyl) -ethylamino] butyl]- 1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 5,11-dihydro-8-chloro-11-[[4- [3-
[(2,2-Dimethyl-1-oxopentyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 5,11-dihydro-8-methyl-11-[[4- [3-
[(2,2-Dimethyl-1-oxopropyl) ethylamino] propyl] -1-piperidinyl] acetyl] -6
H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, 5,11-dihydro-11-[[4- [3-[(2,2-dimethyl-1-oxopropyl) ethyl Amino] propyl] -1-piperidinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 5,11-dihydro-8-methyl-11-[[4- [ Three
-[(2,2-Dimethyl-1-oxobutyl) -ethylamino] propyl] -1-piperidinyl] acetyl]-
A compound of general formula I according to claim 1, which is 6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and salts thereof with inorganic or organic acids. 5. A physiologically acceptable salt of an inorganic or organic acid and a compound according to claims 1-4. 6. At least one fused diazepinone according to claims 1 to 4 or a physiologically acceptable salt according to claim 5 together with conventional carriers and / or excipients. Pharmaceutical formulation. 7. Use of a fused diazepinone according to claims 1-5 for the preparation of a pharmaceutical composition for the treatment of diseases caused by arteriosclerosis of the blood flow in the brain or for the treatment of diseases of the central nervous system. .. 8. Use of a fused diazepinone according to claims 1-5 and 7 for preparing a pharmaceutical composition for enhancing learning ability and improving memory. 9. A) General formula II: embedded image A base-substituted fused diazepinone of the formula (wherein X, B, 1, m, n and R ¹ are as defined in claim 1) in a solvent at a temperature up to the boiling temperature of the reaction mixture has the general formula III: Reacting with a carboxylic acid of R ² —CO—OH (III), where R ² is as defined in claim 1 or a reactive derivative thereof, or b) the general formula IV: ] A diazepinone of the formula (wherein X and B are as defined in claim 1) in a solvent has the general formula V: (Wherein l, m, n, R ¹ and R ² are as defined in claim 1 and Nu represents a nucleophilic group), and then the desired derivative By separating the compounds of general formula I obtained into their diastereomeric or enantiomeric forms and / or converting the salts obtained into the free bases and / or the acid addition of the obtained free bases. Process for the preparation of the novel fused diazepinones of the general formula I according to claims 1 to 5, characterized in that they are converted into salts, more particularly inorganic or organic acids and their physiologically acceptable salts.